Hitherto, extensive research has been made for the study of a sustained-release preparation for the purpose of controlling the releasing rate of a pharmaceutically active agent in the living body thereby obtaining a long-lasting pharmacological activity. For example, sustained-release particulate preparations, in the form of microspheres or microcapsules using a polymeric material such as polylactic acid, polyglycolic acid, etc. which is capable of being decomposed in the living body and is compatible with living tissues, have been proposed.
However, the above conventional preparations have problems in that the production of fine particles having uniform particle size and shape is difficult, and roughness and heterogenity are sometimes formed on the surface of the particles. Another problem of the conventional preparation is that the production of particles having substantially the same particle size with high reproducibility is very difficult.
The above problems associated with the conventional preparations bring about various disadvantages so that the control of the releasing rate of pharmacologically active agents contained therein, which is the most important requirement for the sustained-release preparation, sometimes becomes difficult. As a result, serious side-effects may be noted due to the rapid releasing rate of the active agent, particularly, when the dose level is increased for obtaining a long-lasting pharmacological effect of the active agent. On the other hand, when the releasing rate is too low, the desired pharmacological effect cannot be achieved thereby adversely affecting the therapeutic effect on the disease to be treated with the sustained-release preparation.
The present inventors conducted extensive studies on the sustained-release preparations in order to overcome the above disadvantages of the conventional preparation, in particular, on the selection of polymeric compounds as a basic component which is capable of being degraded in the living body and which is compatible with living tissue, as well as the particle size of the preparation, and, as a result, found that certain types of polymeric compounds can be preferably used as a basic component of the sustained-release preparation. However, with respect to the particle size, it was found that the desired object cannot be achieved without any break-through since particles tend to be integrated or aggregated with each other during the formation of particles.
With respect to the particle size, Japanese Pharmacopea stipulates the maximum particle size of particles to be used in the injectable preparations. That is, in General Rules of Preparation, Item of Injection, it is stipulated that the particle sizes suspended in the preparation of suspension injectable preparations must be 150 .mu.m or less, and, hence, a particle size larger than 150 .mu.m cannot be used for the injectable preparations. For this reason, conventional particles used for suspension injectable preparations must be subjected to a fractionating operation using a sieve for regulating the particle size so as to meet the above regulation of the Japanese Pharmacopea. Apparently, such an operation is time-consuming and expensive since it should be conducted under aseptic and dustfree conditions, and, therefore, an improvement in the production of particulate preparations on an industrial scale has long been desired in the art.